In a longitudinal experimental human P. falciparum infection model where malaria nave volunteers undergo sporozoite challenge, we previously described that malaria induces functionally competent regulatory T cells (Treg) which was associated with reduced pro-inflammatory responses and faster parasite growth. Subsequently, we established that natural exposure to malaria is associated with a transient increase of Treg, that express an effector-memory phenotype and are prone to apoptosis . In a hospital based study investigating children with SM and UM we found that the amount of Treg induced during an acute infection is inversely correlated to the magnitude of malaria specific T cell memory responses, an observation we also confirmed in sporozoite challenged volunteers. Thus, we hypothesize that malaria-specific Treg acquired or activated during a primary infection may limit the magnitude of malaria specific Th1 memory responses to subsequent infections to a level that still allows parasite clearance but with a substantially reduced risk of immunopathology, which may be part of the long sought-after mechanism that protects against SM after minimal exposure only. When a child presents with clinical malaria and consent has been obtained, 1ml of blood will be collected into an RNA preservative. An aliquot of this RNA will be used to measure FOXP3 mRNA and 2 house-keeping genes. Another 4mls (children below 2 years of age) or 8mls (children above 2 years) of blood will be collected into a heparinized tube from which plasma and PBMC will be prepared and cryopreserved. On day 21 (+/- 3 days), a 5 mls blood sample will be collected into a heparinized tube from which plasma and PBMC will be prepared and cryopreserved. At the end of the transmission season 20 secondary severe and 140 age matched secondary uncomplicated cases will be identified. 2.4 million PBMC collected on D0 of the episode preceding the secondary episode will be used for flowcytometric assessment of induced and acquired Tregs and pluripotent T cells. PBMC collected on D21 of the episode preceding the secondary episode will be used to determine malaria specific IFN-gamma/IL-10 memory responses by cultured ELISPOT.